Metformin impairs homing ability and efficacy of mesenchymal stem cells for cardiac repair in streptozotocin-induced diabetic cardiomyopathy in rats

2021 ◽  
Author(s):  
Hania Ibrahim Ammar ◽  
Asmaa Mohammed Shamseldeen ◽  
Heba Samy Shoukry ◽  
Hend Ashour ◽  
Samaa Samir Kamar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Diabetic Patients ◽  
World Population ◽  
Metformin Treatment ◽  
Poor Survival ◽  
Male Wistar Rats ◽  
Multiple Drugs

Bone marrow derived mesenchymal stem cells (BM-MSCs) have demonstrated potential in treating diabetic cardiomyopathy. However, diabetic patients are on multiple drugs and there is lack of understanding on how transplanted stem cells would respond in presence of such drugs. Metformin is an AMP Kinase (AMPK) activator, the widest used anti-diabetic drug. In this study, we investigated the effect of metformin on the efficacy of stem cell therapy in a diabetic cardiomyopathy animal model using streptozotocin (STZ) in male Wistar rats. To comprehend the effect of metformin on the efficacy of BM-MSCs, we transplanted BM-MSCs (1 million cells/rat) with or without metformin. Our data demonstrate that transplantation of BM-MSCs prevented cardiac fibrosis and promoted angiogenesis in diabetic hearts. However, metformin supplementation downregulated BM-MSCs mediated cardioprotection. Interestingly, both BM-MSCs and metformin treatment individually, improved cardiac function with no synergistic effect of metformin supplementation along with BM-MSCs. Investigating the mechanisms of loss of efficacy of BM-MSCs in the presence of metformin, we found that metformin treatment impairs homing of implanted BM-MSCs in the heart and leads to poor survival of transplanted cells. Furthermore, our data demonstrate that metformin mediated activation of AMPK is responsible for poor homing and survival of BM-MSCs in the diabetic heart. Hence, current study confirms that a conflict arises between metformin and BM-MSCs for treating diabetic cardiomyopathy. Approximately 10% of the world population is diabetic to which metformin is prescribed very commonly. Hence, future cell replacement therapies in combination with AMPK inhibitors may be more effective for diabetic patients.

Regeneration of Bone Defects Using Bioactive Glass Combined with Adipose-derived Mesenchymal Stem Cells. An experimental in vivo study

2019 ◽  
Vol 70 (6) ◽  
pp. 1983-1987
Author(s):  
Cristian Trambitas ◽  
Anca Maria Pop ◽  
Alina Dia Trambitas Miron ◽  
Dorin Constantin Dorobantu ◽  
Flaviu Tabaran ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bioactive Glass ◽  
Bone Repair ◽  
Bone Defects ◽  
Calvarial Bone ◽  
Specific Protocol ◽  
Repair Mechanisms ◽  
Male Wistar Rats

Large bone defects are a medical concern as these are often unable to heal spontaneously, based on the host bone repair mechanisms. In their treatment, bone tissue engineering techniques represent a promising approach by providing a guide for osseous regeneration. As bioactive glasses proved to have osteoconductive and osteoinductive properties, the aim of our study was to evaluate by histologic examination, the differences in the healing of critical-sized calvarial bone defects filled with bioactive glass combined with adipose-derived mesenchymal stem cells, compared to negative controls. We used 16 male Wistar rats subjected to a specific protocol based on which 2 calvarial bone defects were created in each animal, one was filled with Bon Alive S53P4 bioactive glass and adipose-derived stem cells and the other one was considered control. At intervals of one week during the following month, the animals were euthanized and the specimens from bone defects were histologically examined and compared. The results showed that this biomaterial was biocompatible and the first signs of osseous healing appeared in the third week. Bone Alive S53P4 bioactive glass could be an excellent bone substitute, reducing the need of bone grafts.

scholarly journals Effects of High Glucose Concentration on Pericyte-Like Differentiated Human Adipose-Derived Mesenchymal Stem Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4604
Author(s):  
Giuliana Mannino ◽  
Anna Longo ◽  
Florinda Gennuso ◽  
Carmelina Daniela Anfuso ◽  
Gabriella Lupo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Mrna Expression ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Angiogenic Factors ◽  
Diabetic Patients ◽  
Ros Production ◽  
Migration Ability ◽  
And Migration

A pericyte-like differentiation of human adipose-derived mesenchymal stem cells (ASCs) was tested in in vitro experiments for possible therapeutic applications in cases of diabetic retinopathy (DR) to replace irreversibly lost pericytes. For this purpose, pericyte-like ASCs were obtained after their growth in a specific pericyte medium. They were then cultured in high glucose conditions to mimic the altered microenvironment of a diabetic eye. Several parameters were monitored, especially those particularly affected by disease progression: cell proliferation, viability and migration ability; reactive oxygen species (ROS) production; inflammation-related cytokines and angiogenic factors. Overall, encouraging results were obtained. In fact, even after glucose addition, ASCs pre-cultured in the pericyte medium (pmASCs) showed high proliferation rate, viability and migration ability. A considerable increase in mRNA expression levels of the anti-inflammatory cytokines transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) was observed, associated with reduction in ROS production, and mRNA expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and angiogenic factors. Finally, a pmASC-induced better organization of tube-like formation by retinal endothelial cells was observed in three-dimensional co-culture. The pericyte-like ASCs obtained in these experiments represent a valuable tool for the treatment of retinal damages occurring in diabetic patients.

scholarly journals Uncarboxylated osteocalcin alleviates the inhibitory effect of high glucose on osteogenic differentiation of mouse bone marrow–derived mesenchymal stem cells by regulating TP63

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Fangzi Gong ◽  
Le Gao ◽  
Luyao Ma ◽  
Guangxin Li ◽  
Jianhong Yang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
High Glucose ◽  
Bone Development ◽  
Inhibitory Effect ◽  
Osteoblastic Differentiation ◽  
Diabetic Patients ◽  
Mouse Bone Marrow

Abstract Background Progressive population aging has contributed to the increased global prevalence of diabetes and osteoporosis. Inhibition of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by hyperglycemia is a potential pathogenetic mechanism of osteoporosis in diabetic patients. Uncarboxylated osteocalcin (GluOC), a protein secreted by mature osteoblasts, regulates bone development as well as glucose and lipid metabolism. In our previous studies, GluOC was shown to promote osteoblastic differentiation of BMSCs; however, the underlying mechanisms are not well characterized. Tumor protein 63 (TP63), as a  transcription factor, is closely related to bone development and glucose metabolism. Results In this study, we verified that high glucose suppressed osteogenesis and upregulated adipogenesis in BMSCs, while GluOC alleviated this phenomenon. In addition, high glucose enhanced TP63 expression while GluOC diminished it. Knock-down of TP63 by siRNA transfection restored the inhibitory effect of high glucose on osteogenic differentiation. Furthermore, we detected the downstream signaling pathway PTEN/Akt/GSK3β. We found that diminishing TP63 decreased PTEN expression and promoted the phosphorylation of Akt and GSK3β. We then applied the activator and inhibitor of Akt, and concluded that PTEN/Akt/GSK3β participated in regulating the differentiation of BMSCs. Conclusions Our results indicate that GluOC reduces the inhibitory effect of high glucose on osteoblast differentiation by regulating the TP63/PTEN/Akt/GSK3β pathway. TP63 is a potential novel target for the prevention and treatment of diabetic osteoporosis.

scholarly journals The Compromised Anti-microbial Function of Mesenchymal Stem Cells in Diabetic Patients

2017 ◽  
Vol 2 (3) ◽  
pp. 2473011417S0004
Author(s):  
Zijun Zhang ◽  
Lew Schon ◽  
Young Cho
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bacterial Infection ◽  
Conditioned Medium ◽  
Culture Media ◽  
Cell Metabolism ◽  
Diabetic Group ◽  
Diabetic Patients ◽  
Paracrine Factors ◽  
E Coli

Category: Basic Sciences/Biologics Introduction/Purpose: Diabetic foot infection (DFI), including skin infection and osteomyelitis, is a severe complication of late- stage diabetes. Mesenchymal stem cells (MSCs) facilitate bacterial clearance. In bacterial infection, MSCs, via paracrine mediators, regulate the host cell metabolism and inflammatory response. Particularly, MSCs augment the antibacterial function of neutrophils. It is generally believed that hyperglycemia in diabetes is toxic to MSCs/progenitors and detrimental to their regenerative function. It is unknown, however, whether the antibacterial function of MSCs is compromised in diabetes. Methods: Bone marrow samples from 6 diabetic and 4 non-diabetic patients (approved by IRB) were used for MSC isolation. 1. MSCs from both diabetic and non-diabetic patients were treated with lipopolysaccharides (LPS), a bacterial wall component, for 6 hours. The tissue culture media were collected as conditioned medium. E. coli from a single colony were cultured with addition of the conditioned medium generated by either diabetic or non-diabetic MSCs and inoculated on LB-agar plates overnight. Bacterial colonies were counted. 2. Human macrophages were isolated from umbilical cord blood and co-cultured with either diabetic or non-diabetic MSCs, in a trans-well system, for 24 hours. The macrophages were then cultured with heat-inactivated E. coli for one hour. After extensive washing, macrophage and bacteria were stained with Pappenheim method. Bacterial phagocytosis of macrophages, after co- cultured with diabetic or non-diabetic MSCs, was assessed under a microscope. Results: There was no statistical difference in the number of E. coli colonies when regular medium produced by diabetic and non- diabetic MSCs was added into the bacterial culture. When the diabetic and non-diabetic MSCs were treated with LPS and the conditioned medium was collected and added into bacterial cultures, E. coli colonies increased in the diabetic group, about 3 fold, as compared with the non-diabetic group (p < 0.05). Macrophages were counted in defined areas of the Petri dishes and designated as infected or uninfected, according to the presentation of bacterial bodies or not. While the infection rate of macrophages co-cultured with non-diabetic MSCs was 85% (±5.5%), it was 70% (±6.6%) when macrophages were co-cultured with diabetic MSCs (p = 0.006). Conclusion: MSCs-produced paracrine factors suppressed the growth of E. coli but diabetic and non-diabetic MSCs had no difference in such a function. Activation with LPS did not augment the non-diabetic MSCs but weakened diabetic MSCs in suppression of bacterial growth. MSCs regulate macrophages in bacterial phagocytosis. Diabetic MSCs, however, had a limited role in regulation of macrophages. This study demonstrated that MSCs in diabetic patients are compromised in anti-bacterial infection. The results not only deepen the understanding of bacterial infection in diabetes but also open up new strategy to control bacterial infection in diabetic patients.

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